Platform developed at Cedars-Sinai to test endocrine disruptors’ effects

Friday, 11 August, 2017, 08 : 00 AM [IST]

Sareen Los Angeles

Three chemicals added to breakfast cereals and other foods may be making people obese. These were the findings of a new study, which detailed how Cedars-Sinai investigators developed a novel platform and protocol for testing the effects of these chemicals, known as endocrine disruptors, on humans.

Butylhydroxytoluene (BHT), perfluorooctanoic acid (PFOA) and tributyltin (TBT), the three chemicals tested in this study - which was published in Nature Communications - are abundantly found.

While BHT is an antioxidant commonly added to breakfast cereals and other foods to protect nutrients and keep fats from turning rancid, PFOA is a polymer found in some cookware, carpeting and other products, and TBT is a compound in paints that can make its way into water and accumulate in seafood.

Experiments were conducted to test the effects of these chemicals on animals, and growing evidence from these suggested that there may be a link between their addition to foods and obesity.

However, until now, there were a number of obstacles in confirming these findings in humans.

The investigators used hormone-producing tissues grown from human stem cells to demonstrate how chronic exposure to these chemicals could interfere with signals sent from the digestive system to the brain that let people know when they were full during meals. Despite a breakdown in this signalling system, people would often continue eating, causing them to gain weight.

“We discovered that each of these chemicals damaged hormones that communicate between the gut and the brain,” said Dhruv Sareen, assistant professor, bio-medical sciences, and director, Induced Pluripotent Stem Cell Core Facility, Cedars-Sinai Board of Governors Regenerative Medicine Institute.

“When we tested the three together, the combined stress was more robust,” he added.

“Of the three chemicals tested, BHT produced some of the strongest detrimental effects,” Sareen said.

“While other scientists have shown these compounds can disrupt hormone systems in laboratory animals, the new study is the first to use human pluripotent stem cells and tissues to document how the compounds may disrupt hormones that are critical to gut-to-brain signalling and preventing obesity in people,” he added.

“This is a landmark study that substantially improves our understanding of how endocrine disruptors may damage human hormonal systems and contribute to the obesity epidemic in the United States,” said Clive Svendsen, director of the institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine.

According to federal statistics, more than one-third of adults in the United States are considered to be obese.

“The new testing system developed for the study has the potential to provide a much-needed, safe and cost-effective method that can be used to evaluate the health effects of thousands of existing and new chemicals in the environment,” the investigators said.

For their experiments, Sareen and his team first obtained blood samples from adults, and then, by introducing reprogramming genes, converted the cells into induced pluripotent stem cells.

Then, using these stem cells, the investigators grew human epithelium tissue, which lines the gut, and neuronal tissues of the brain's hypothalamus region, which regulates appetite and metabolism.

The investigators then exposed the tissues to BHT, PFOA and TBT, one by one and also in combination, and observed what happened inside the cells.

They found that the chemicals disrupted networks that prepare signalling hormones to maintain their structure and be transported out of the cells, thus making them ineffective.

The chemicals also damaged mitochondria — cellular structures that convert food and oxygen into energy and drive the body’s metabolism.

“Because the chemical damage occurred in early-stage young cells, the findings suggest that a defective hormone system could impact a pregnant woman as well as her foetus in the womb,” Sareen said.

“While other scientists have found, in animal studies, that effects of endocrine disruptors can be passed down to future generations, this process has not been proved to occur in humans,” he added.

According to the National Toxicology Programme of the United States Department of Health and Human Services, more than 80,000 chemicals are registered for use in the United States in everyday items such as foods, personal care products, household cleaners and lawn-care products.

While the programme stated on its website that relatively few chemicals were thought to pose significant risks to human health, it added, “We do not know the effects of many of these chemicals on our health.”

Cost and ethical issues, including the health risk of exposing human subjects to possibly harmful substances, were among the barriers to testing the safety of many chemicals.

As a result, numerous widely-used compounds remained unevaluated in humans for their health effects, especially to the hormone system.

“By testing these chemicals on actual human tissues in the lab, we potentially could make these evaluations easier to conduct and more cost-effective,” Sareen said.

He was the principal investigator for the study, while research scientist Uthra Rajamani was the first author.

The research reported in this publication was supported by the National Centre for Advancing Translational Science of the National Institutes of Health.